In mammals, a large number of enzymes exist that metabolize drugs and other xenobiotics. Cytochrome P450s are among the most important of these enzymes and they are known to be involved in metabolism of most therapeutically-used agents. The P450s are also critical in the metabolic-activation of promutagens and procarcinogens. P450s known to metabolize xenobiotics are found in the CYP1, CYP2 and CYP3 families. Each of these families consist of two or more subfamilies containing the individual P450 forms. One question that has not been directly addressed is whether P450s are required for chemical carcinogenesis in an intact animal. The fact that P450s can metabolically-activate procarcinogens implies that they are involved in the process of chemical carcinogenesis. However, the only experiments suggestive of a role for P450s in cancer etiology are indirect chemically-induced transformation assays in cell culture, and genetic experiments in mice involving the Ah locus. However, no direct evidence is available to establish that P450s are necessary for carcinogenesis in an intact animal model system. To assess the physiological role, if any, for P450s and their potential contribution to the process of chemical carcinogenesis, P450-null mice were produced. CYP1A2 and CYP2E1-null mice were indistinguishable from mice having the P450s, indicating that they have no critical role in mammalian development or physiological homeostasis. Pharmacokinetic studies using caffeine showed rat CYP1A2 is responsible for metabolism of this drug and that metabolism is rate limiting for its urinary excretion. The CYP2E1-null mice were found to be resistant to the toxicity of acetaminophen and benzene as compared to normal mice indicating that CYP2E1 is the principal P450 involved in-metabolic activation of these chemicals. Carcinogenesis bioassays are currently in progress to determine the role of P450s in the hepatocarcinogenesis of various chemicals including 4-aminobiphenyl, food mutagens and phenacetin.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Cheng, Jie; Krausz, Kristopher W; Li, Feng et al. (2013) CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid. Toxicol Appl Pharmacol 266:245-53
Holmstock, Nico; Gonzalez, Frank J; Baes, Myriam et al. (2013) PXR/CYP3A4-humanized mice for studying drug-drug interactions involving intestinal P-glycoprotein. Mol Pharm 10:1056-62
Cheng, Jie; Ma, Xiaochao; Krausz, Kristopher W et al. (2009) Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity. Drug Metab Dispos 37:1611-21
Liu, Aiming; Patterson, Andrew D; Yang, Zongtao et al. (2009) Fenofibrate metabolism in the cynomolgus monkey using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics. Drug Metab Dispos 37:1157-63
Cho, Joo-Youn; Kang, Dong Wook; Ma, Xiaochao et al. (2009) Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation. J Lipid Res 50:924-37
Patterson, Andrew D; Slanar, Ondrej; Krausz, Kristopher W et al. (2009) Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation. J Proteome Res 8:4293-300
Dostalek, Miroslav; Hardy, Klarissa D; Milne, Ginger L et al. (2008) Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J Biol Chem 283:17147-57
Dragin, Nadine; Shi, Zhanquan; Madan, Rajat et al. (2008) Phenotype of the Cyp1a1/1a2/1b1-/- triple-knockout mouse. Mol Pharmacol 73:1844-56
Smith, N F; Baker, S D; Gonzalez, F J et al. (2008) Modulation of erlotinib pharmacokinetics in mice by a novel cytochrome P450 3A4 inhibitor, BAS 100. Br J Cancer 98:1630-2
Chen, Chi; Shah, Yatrik M; Morimura, Keiichirou et al. (2008) Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis. Cell Metab 7:135-47

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